间变性淋巴瘤激酶（ALK）融合基因在多种血液及实体瘤中发现，约4-7%非小细胞肺癌存在ALK融合基因突变。融合基因具有致癌性，肿瘤表现ALK依赖，因而ALK融合基因是良好的肺癌治疗靶点。然而，ALK融合基因诱导肿瘤形成的确切机制目前仍未阐明。我们最近观察到：ALK融合基因除内源性促进肿瘤细胞增殖外，上调肺癌细胞中S100A8/9等多个炎症因子表达，后者参与髓源性抑制细胞（MDSC）募集及扩增，从而介导肿瘤免疫逃逸，促进肿瘤形成。本课题拟：（1）进一步系统分析ALK调控的炎症因子，揭示调控涉及的信号通路；（2）阐明S100A8/9等炎症因子介导的MDSC生成效应及机制；（3）明确MDSC促肿瘤效应及机制；（4）评价ALK肺癌患者中S100A8/9等炎症因子表达、MDSC生成、ALK肺癌病人预后的相关性。本课题有助于揭示ALK诱导肿瘤形成的机制，为治疗ALK肺癌提供新思路。

Anaplastic lymphoma kinase (ALK) fusion genes have been identified in multiple types of hematological and solid tumor with the presence of ALK fusion gene in about 4-7% patients with non-small cell lung cancer. ALK fusion genes are oncogenic and ALK-positive tumor display ALK oncogene addiction, which makes ALK oncogene an excellent target for the treatment of lung cancer. At present, however, the mechanisms underlying the tumorigenesis induced by ALK oncogene are poorly understood. Our recent findings show that other than endogenously promoting the proliferation of tumor cells, ALK oncogene controls the expression of a serial of inflammatory cytokines, which can induce the recruitment and expansion of myeloid-derived suppressor cells (MDSC) and consequent MDSC-mediated cancer immune evasion. In this study, we aim to focus on the following aspects:(1) systematically analyze the induction of and related signaling pathways responsible for the expression of inflammatory cytokines modulated by ALK oncogene;(2) clarify the effect of ALK-induced inflammatory cytokines on and pinpoint to the key factors and associated signaling pathways responsible for the accumulation of MDSC;(3) explore the protumorigenic effects and mechanisms conferred by MDSC; and (4) evaluate the correlation between the levels of S100A8/9, MDSC accumulation and the clinical prognosis in the patients with ALK-positive lung cancer. Our results will shed a new light on the mechanisms by which ALK oncogene induces carcinogenesis and provide new ideas for the treatment of ALKoma.

间变性淋巴瘤激酶（ALK）融合基因在多种血液及实体瘤中发现，约4-7%非小细胞肺癌存在ALK融合基因突变。融合基因具有致癌性，肿瘤表现ALK依赖，因而ALK融合基因是良好的肺癌治疗靶点。然而，ALK融合基因诱导肿瘤形成的确切机制目前仍未阐明。我们前期观察到ALK融合基因能够上调肺癌细胞中具有髓源性抑制细胞（MDSC）募集/扩增功能的多个炎症因子表达，从而提出ALK融合通过诱导MDSC扩增募集促进肿瘤免疫逃逸的科学假设。该研究中我们系统阐明了ALK融合基因通过调控炎症因子分泌促进MDSC扩增募集从而促进肿瘤免疫逃逸的细胞及分子机制。我们发现EML4-ALK融合基因能够诱导肺癌细胞S100A8、S100A9和CCL2表达，信号通路抑制剂阻断实验显示这种诱导有赖于ALK下游激活的STAT3信号，荧光素酶报告实验显示活化STAT3能够直接与上述基因的启动子区结合，促进这些基因的表达。体外诱导分化实验显示S100A8/9能够促进骨髓前体细胞或单核前体细胞向MDSC分化；体外趋化实验显示CCL2能够趋化MDSC细胞。小鼠体内实验显示，采用抗体阻断S100A8/9和CCL2活性能够减少瘤内MDSC聚集，抑制肿瘤生长。进一步检测ALK融合基因阳性肺癌患者发现，患者肿瘤组织中存在S100A8/9和CCL2表达，并与STAT3磷酸化（pSTAT3）直接相关，患者血浆中S100A8/9和CCL2水平与外周MDSC的水平呈正相关，初步明确ALK-STAT3- S100A8/9/CCL2-MDSC轴的临床相关性。我们的研究结果揭示了ALK融合基因诱导肺癌形成的新机制，为ALK肺癌的治疗提供了新思路。